Dr. Sweatt's laboratory pioneered the research that discovered the important role of one particular signaling pathway, the ERK pathway, in the consolidation of hippocampus-dependent memory. The laboratory has discovered an additional, necessary step, histone acetylation, a post-translational modification and epigenetic mechanism that regulates gene transcription. Contextual fear conditioning (CxFC) is associated with an increase in histone acetylation. The research proposed here is intended to investigate the role of another epigenetic mechanism, DNA methylation, in the regulation of histone acetylation and three equally important components of memory, consolidation, retrieval and reconsolidation. The central hypothesis is that DNA methylation serves as an important regulator of the brain's ability to store, recall and modulate memories through regulation of chromatin structure. The proposed specific aims will explore the role of DNA methylation in learning & memory. Currently, our understanding of memory formation and storage involves changes to gene transcription and synaptic proteins. However, the results of the experiments proposed here have the potential to reveal a novel and exciting concept-that learning brings about changes at the level of an individual's DNA. Specific Aim 1: To investigate a role for DNA methylation in memory consolidation and regulation of chromatin structure. A variety of approaches will be used, including assessing changes in methylation of target genes, regulation of methyltransferases (DNMT), and the effect of DNMT inhibition on CxFC. This will be complemented by studies of epigenetic manipulations on synaptic plasticity and testing of the hypothesis that DNA methylation controls histone post-translational modifications both in vitro and in vivo. Specific Aim 2: To characterize a potential role for histone acetylation and DNA methylation in hippocampus-dependent retrieval and reconsolidation. Retrieval and reconsolidation are important memory mechanisms, with implications for a variety of memory disorders. Using techniques similar to those employed in specific aim 1, I will first investigate a role for histone acetylation and DNA methylation in memory retrieval. If histones are acetylated and/or DNA is actively methylated during retrieval, it is likely they play a role in reconsolidation, a process in which retrieved memories are made transiently unstable and, thus, susceptible to disruption. I will then investigate the role of DNA methylation and histone acetylation in reconsolidation of memory for CxFC. An understanding of these processes may identify novel therapeutic targets for disorders involving both compromised and aberrantly strong learning and memory, including autism spectrum disorders, schizophrenia, PTSD and drug addiction. [unreadable] [unreadable] [unreadable]